Project Abstract Chronic Rhinosinusitis (CRS) is a leading cause of morbidity globally with symptoms such as nasal congestion, rhinorrhea, and discharge. It is the single most common self-reported chronic health condition and accounts for billions of dollars in health care costs and lost work days annually. Exposure to air pollutants is thought to be a critical modifier of CRS susceptibility. Despite marked reductions in air pollution levels in the United States, the fine particulate component of air pollution [PM <2.5 ? (PM2.5)] and ultrafine pollutants secondary to traffic continue to remain a recalcitrant issue in many counties in the United States. PM2.5 promotes oxidative stress and inflammation in the mucosal lining of the nose and sinuses contributing to sinonasal epithelial barrier disruption. As a physician-scientist, through my K23, I developed a strong rationale for the scientific premise of this proposal to investigate the critical role of Nuclear related factor-2 (Nrf2) dependent host defense as a modifier of CRS. As a new investigator, I am now in the process of transitioning from a K23 award to independent funding. My preliminary studies have indicated that the transcription factor, Nrf2 is involved in the upregulation of an array of anti-oxidant and anti-inflammatory gene programs involved in the preservation of epithelial integrity. Furthermore, our preliminary results have indicated that chronic PM2.5 exposure causes suboptimal Nrf2 host defense that may lead to CRS. Our central hypothesis in this proposal is that Nrf2 plays a critical role in epithelial cell hypersensitivity to PM2.5 and modulation of epithelial barrier function in patients leading to CRS. We have assembled a multidisciplinary team of experts and propose aims using mice and humans. In SA1, we will test this hypothesis using a novel animal model of CRS, models of Nrf2 over-expression and deficiency and state of the art in-vivo animal PM2.5 exposure system to mimic levels of PM2.5 relevant to humans. We will also analyze expression of sinonasal epithelial tight junctional proteins. SA2 will determine the mechanism by which PM induces epithelial barrier dysfunction and Nrf2 ameliorates this permeability using human sinonasal epithelial cells and a novel PM2.5 cell culture exposure system. Lastly, SA3 will determine if chronic PM2.5 exposure can cause epigenetic modifications in the sinonasal mucosa affecting Nrf2 transcription. Our results will provide much needed translational data to target potential treatment targets in CRS and contribute to our knowledge of this poorly understood disorder.